The long-term objectives of this proposal are to understand the molecular pathways that are essential to maintain the viability and function of dopamine neurons of the substantia nigra in the mature central nervous system. Our interest in this group of neurons is based on their selective vulnerability to the degeneration that occurs in Parkinson[unreadable]s disease (PD) and related disorders. While many neuronal groups are affected by the disease, it is the loss of this group that results in the well-known motor disabilities associated with the disease. While there are many treatments available today that improve the motor impairments, none of them forestall the relentless progression of the condition. Our long-term objectives are founded on the belief that the discovery of treatments that will successfully forestall progression will derive only from an improved understanding of the molecular processes that are essential for maintenance of neuron viability in the mature brain, and of the processes that mediate their demise when these conditions fail. Our specific goals in this proposal are to define the role played by the neurotrophic factors GDNF and BDNF in maintaining the viability of dopamine neurons of the substantia nigra during development and in adulthood. While GDNF itself has attracted much interest for possible direct use in the treatment of PD, recent unsuccessful clinical trials indicate that GDNF alone is unlikely to provide therapeutic benefit. However, it is reasonable to postulate that if we can define the precise role of endogenous GDNF and BDNF in providing neurotrophic support for dopamine neurons, and the signaling pathways that they use, then we may be able to develop more potent approaches. Furthermore, definition of critical survival signaling pathways may offer clues to underlying pathogenesis, because there is growing evidence that the disease may be primarily a failure of these pathways. We will investigate the roles of these neurotrophic factors and their signaling pathways in three Specific Aims. In the first Aim, we will use state-of-the-art conditional gene deletion technologies to ablate expression of either GDNF or its receptor GFR&#945;1 selectively within the striatal target or the substantia nigra, respectively, during a critical period of developmental cell death. In this Aim, we will also investigate the striatum as the source of GDNF that is essential for the survival of dopamine neurons in adulthood. In the second Aim, we will again use refined conditional gene deletion techniques to determine whether local mesencephalic expression of BDNF is essential to maintain the viability of adult dopamine neurons. In the third and final Aim, we will use conditional gene deletion to determine the role of PDK1, a master regulator of the AGC family of kinases in maintaining the viability of dopamine neurons during development and in adulthood.